Robotic syringe system utilizing a liquid piston for the measurement and dispensing of fluid samples

ABSTRACT

Described here is a mechanical and electronic device which can accurately draw up and dispense a volume of fluid. A novel syringe is described which can replace (and overcome some of the shortfalls) of the traditional mechanical syringe by way of a liquid syringe. The syringe system is designed to be used in conjunction with modern liquid handling systems used in biological and biochemical research as related to drug screening. However, the syringe system is not limited to such applications. Also of key importance to this invention, is the use of a monitoring system to accurately monitor and record the actual volumes being drawn up and dispensed. The liquid piston has the advantage of reduced friction and removes the necessity for there to be any o-ring or sealing system which requires periodic replacement and/or maintenance.

RELATED APPLICATIONS

This application claims the benefit of prior filed Provisional Application No. 60/559,419.

FIELD

This invention relates to a system for accurately and consistently measuring a volume of fluid. In particular, this invention relates to a system which can measure and dispense liquid samples for use in biochemical and pharmaceutical assays. This invention describes a novel syringe pump for the suction and dispensing of fluids.

DESCRIPTION OF THE PRIOR ART

The concept of a syringe pump has been under development and modification for several years. However, in all cases, the syringe pump has several common features. First, the syringe pump has some sort of syringe barrel, which can be described as a short tube with an opening at each end. One opening serves as the orifice for fluid samples to go in and out and the other serves as the access point for the other major component, the syringe plunger or piston. The piston serves to move inside the barrel such that when the piston is moved further into the barrel a positive pressure is produced and any fluid in the barrel is removed. Conversely, when the piston is drawn out of the syringe barrel a negative pressure or a vacuum is produced, which serves to provide suction and draw up any fluid in contact with the orifice at the other end of the barrel.

During either the suction or dispensing of fluids, the volume dispensed or drawn up can be monitored as the distance that the piston moves inside the barrel. This distance is proportional to the volume of sample liquid. For example, if the piston doubles its distance, twice as much liquid would be either dispensed or sucked up. Thus, the volume of liquid can be monitored or controlled by controlling or monitoring the distance that the piston moves inside the barrel. Because of this, it is very important that the syringe barrel be of uniform shape and that the control of the movement is very precise.

The piston must serve to seal with the barrel such that the necessary pressures can be produced and maintained appropriately. This is often done using some sort of rubber seal or o-ring. The movement of the piston inside the barrel can be achieved using several different mechanical and electro-mechanical devices including motors, solenoids, and other devices. There are also several other adaptations and improvements that can be made on the design, including those in U.S. Pat. Nos. 5,896,804 and 6,500,151.

BACKGROUND OF THE INVENTION

In the modern pharmaceutical company it is not uncommon to have libraries of several million compounds. These libraries are used in a variety of biological tests (such as cell based assays or binding assays) to test for the ability of these compounds to have some pharmaceutical property. Eventually, after many months of testing and development, one or two compounds out of a library of millions may become a clinically tested drug. The early screening of these libraries is done using a variety of assays, all of which require some form of liquid handling and accurate liquid measurement.

With such libraries of compounds, the accurate automation of fluid dispensing and measurement is key. Also of importance, is the ability of such liquid handling systems to be able to monitor the fluid delivered. This would allow the user to either be notified of a problem or to track some problem if it was suspected. Another problem faced by such liquid handling systems, is the fact that their syringe pistons have to mechanically seal with the syringe barrel. This is usually done with an o-ring type device as stated. These sealing systems are prone to failure and fatigue; therefore requiring constant monitoring and maintenance.

A device incorporating a liquid piston moving inside a solid syringe barrel would be able to accurately measure and dispense fluid samples and would not have the typical limitations of the traditional liquid handling devices. There would be no need to deal with any of the problems of friction, wear and tear, and as described below, it is possible to very simply monitor the volume of fluid measured and dispensed by such a device. A further advantage of this device is the reduction in the number of mechanical and moving parts.

BRIEF SUMMARY OF THE INVENTION

The object of the present invention is to provide a new syringe pump design which utilizes a liquid piston instead of the traditional solid or mechanical piston. The liquid piston can be moved and controlled by a number of devices and setups. These include control by applying different pressure sources to a liquid piston by way of electronic valves. The liquid piston will be in contact with these different sources which are capable of moving the liquid piston into or out of the syringe barrel. The piston could also be controlled using such things as a two-way gear pump or other device capable of supplying more or less of the same liquid that makes up the syringe piston. The liquid piston would serve a similar purpose as the traditional piston except that it would have several advantages including: little or no friction related problems, capabilities for very small volumes (tests have shown easy measurement of nano-liter volumes), and easy adaptation for multiple syringes (for example 96 micro-syringes in a eight by twelve array).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is sketch of the liquid piston and its associated parts. A liquid piston is shown, including the syringe barrel, the sample, an air gap, and a device to provide movement of the piston into and out of the syringe barrel.

DETAILED DESCRIPTION OF THE PREFFERRED EMBODIMENT

Described below is a preferred embodiment of the liquid piston syringe pump and the accompanying mechanical and electronic devices needed to ensure proper performance.

Liquid Piston

The key to the device is the use of a liquid piston which serves to move in and out of the syringe barrel (FIG. 1). It is important to note that there is an air gap between the liquid piston and the sample. This liquid piston is composed of a liquid which has several important properties as follows:

1) It must be sufficiently opaque in order for it to be picked up by a camera (CCD or equivalent) or other optical device.

2) Its volume should not change significantly with respect to pressure changes.

3) It should have the appropriate physical properties to function correctly as a liquid piston (see description below).

The liquid piston must also have a very high boiling point and it must have the correct viscosity. If the liquid piston is too thick, it will not be able to move in and out of the syringe barrel quick enough. If the liquid used is to thin, it may not be able to stay in the syringe barrel and become mixed up with samples. Another important quality which must be considered is the affinity of the piston material for the side walls of the syringe barrel. If the affinity is too high, there will likely be contamination of the piston material with the samples. This means that one must choose very carefully the material with which to make the syringe barrel. Some materials which would work well depending on the choice of barrel material would be water, oil, or other. The diameter of the syringe barrel is also very important. If the diameter is too large, the liquid piston will not function properly and will leak out of the barrel. If the diameter is too small, the pressures required to move the piston in and out of the syringe will be extremely high and cause movement of the syringe piston to be too restricted.

Piston Motion

The movement of the piston into and out of the syringe barrel could be accomplished through various techniques. In one embodiment, vacuum and positive pressure sources would serve to move the piston into and out of the syringe barrel. These pressure sources must be constant and be able to reliably provide pressure consistently over long periods of time. Each of the pressure sources would be attached to a reservoir of the liquid which is chosen to make up the liquid piston. The reservoir would be sufficient such that the change in the reservoir volume would not be significant as the liquid piston moved into and out of the barrel. Each reservoir would be attached to the liquid piston via valves. The pressure in each of the two pressure systems would be maintained using some type of pump. One would use a positive pressure pump, and the other would use a negative pressure pump. It is important that each of the pumps has a very good feed-back control loop.

Other embodiments which could serve to move the piston into and out of the syringe barrel would be other fluid moving devices such as a gear pump, which are known to those skilled in the art. Essentially, it is two intermeshing gears which are capable of pumping fluid in two directions.

Valves

The application of either positive pressure or vacuum as described in one of the embodiments above is controlled using a set of computer controlled valves. One valve provides connection between the piston and the positive pressure source and the other provides connection between the piston and the vacuum source. Therefore, if the positive pressure source valve is turned on, the liquid will flow towards the syringe barrel and the liquid syringe will move into the syringe barrel. If there were liquid in the syringe barrel, it would be forced out of the syringe at a rate proportional to the distance that the fluid moved.

Conversely, if the vacuum source valve were opened, then the liquid would move away from the barrel and the piston would be moved out of the syringe barrel. This could serve to suck liquid up into the syringe.

Volume Monitoring

As explained above, the distance that the syringe moves inside the barrel is proportional to the volume that can be sucked up or released. Therefore, being able to measure and monitor this distance moved allows a person to monitor and measure the volume. One way which this distance can be accurately monitored is through the use of CCD (charge-coupled device) camera(s).

The CCD camera could be placed next to the syringe barrel and would be able to monitor the position of the liquid piston using the appropriate electronics and computer systems. Therefore the syringe position and valve opening and closing could be part of a feedback loop system to allow precise control of volumes delivered or aspirated.

Of critical importance to correct function of the CCD monitoring system, is the use of a syringe barrel which is transparent and a fluid for the liquid piston which is opaque enough to allow proper monitoring by the CCD camera. The relationship between distance moved and volume would need to be determined experimentally depending upon the liquid that is being sucked up and dispensed.

Control Systems

The required valves and vacuum systems or other devices used to monitor and control the liquid piston are of such nature that they can be controlled and adjusted using computerized systems and the appropriate electronics. For example, a personal computer with the appropriate data acquisition card would be capable of carrying out the appropriate control protocols.

Other Embodiments and Advances

An important advantage of this system is that it allows for two other advances. First, it is possible to make extremely small syringes. The traditional mechanical syringe piston limits the size of the syringe that can be used. However, there is no practical size limit associated with the use of a liquid syringe. The second advancement is associated with this size advantage. That is, it is possible to create an array of small syringes, which are all connected to the same piston driving system (i.e. pressure sources or gear pump). One can envision using an array of syringes which would be able to dispense into and take from the popular multi-well plates used in pharmacological assays. The most common plates have 96, 384, or 1536 wells. For example, an array of 384 liquid piston syringes could be used to take liquid out of or place liquid into such a 384 well plate. 

1. A syringe pump comprising a mechanism for engaging and driving a plunger of a syringe inside a syringe barrel and where said plunger is comprised of a liquid.
 2. The system according to claim 1, wherein said mechanism for engaging and driving the said liquid plunger consists of two reservoirs of the same liquid and one reservoir is under a pressure greater then the ambient pressure (a pressure source) and one reservoir is under a pressure less then the ambient pressure (a vacuum source); and a. where said mechanism consists of two valves connecting the said reservoirs to the said plunger such that the said plunger's motion can be controlled inside the said syringe barrel using the valves; and b. where the pressures of the said reservoirs are kept constant; and c. where the position of the said plunger can be monitored to control the volume delivered by the syringe pump.
 3. The system according to claim 1, wherein said mechanism for engaging and driving the said liquid plunger consists of a gear pump.
 4. The system according to claim 2, wherein the said syringe pump can aspirate a solution by opening of the valve connected to the said vacuum source, effectively moving the said plunger out of the syringe barrel.
 5. The system according to claim 2, wherein the said syringe pump can dispense a solution by opening of the valve connected to the said pressure source, effectively moving the said plunger into the syringe barrel.
 6. The system of claim 5, wherein the time the said valve is open is proportional to the total volume that is dispensed by the syringe.
 7. The system of claim 2, wherein the said valves are controlled using solenoids and pulsed width modulation.
 8. The system according to claim 1, wherein the said barrel is of diameter 0.1 millimeter to 20 millimeter.
 9. The system according to claim 1, wherein the said barrel is composed of a transparent glass or plastic.
 10. The system according to claim 1, wherein said liquid is composed of a liquid with a suitable opacity, viscosity, and boiling point.
 11. The system according to claim 1, wherein the said liquid is one of water and oil.
 12. An optical detection system to monitor the position of a syringe plunger consisting of: a. a charge-coupled device (CCD) camera able to detect the position of the liquid piston; and b. where the distance that the piston moves can be related by mathematical equations to the volume of liquid either aspirated or dispensed. 